Identification of specific molecules which become induced or activated after work load is increased would contribute to understanding the hierarchical mechanism for cardiac hypertrophy triggered by hypertension or structural heart disease. Although underlying mechanisms of such cardiac hypertrophy remain obscure, previous studies indicate that trophic factors may accumulate in the myocardium during the onset and maintenance of cardiac hypertrophy following experimental pressure overload, ischemia and infarction. The applicant hypothesizes that insulin like growth factor (IGF) through autocrine/paracrine mechanisms provides long term cardiac muscle hypertrophy. IGF-I represents a growth factor which consistently potentiates the growth of sarcomeric tissues. Several tissues, including the heart and skeletal muscle, synthesize and secrete IGF-I and cognate IGF binding proteins to form complexes which stabilize IGF-I from rapid turnover. IGFBP could also act as potentiators or inhibitors of IGFs biological activity through interaction with cell surface IGF-I receptors, a ligand-activated-tyrosine kinase. High levels of circulating IGF-I are associated with a high incidence of cardiac hypertrophy in human acromegalic patients. Thickening of blood vessel walls and left ventricular hypertrophy observed in genetic-hypertensive animals correlate well with increased local production of IGF-I. Enhanced cardiac expression of IGF-I follows rapidly after aortic banding and introduction of IGF-I into cultured cardiac myocytes activate skeletal-actin (SkA) and the fetal gene programs. The applicant has determined that multiple copies of the serum response element (SRE) are required for SkA promoter activity in cardiomyogenic cell types. SRF and another factor, F-ACT1/YY1, bind in a mutually exclusive manner over the proximal SRE1. SRF has been shown to transactivate the SkA, while YY1 acts as a potent repressor. The applicant found that IGF-I transactivates the SkA promoter in myogenic cells requiring intact SREs. Recent studies show that ternary complex formation with an accessory factor, Elk-1, is required for growth factor induced activation. As a general strategy to determine the biological role of IGF-I in cardiac hypertrophy, the applicant proposes to intervene in the signaling cascade with reagents which either block or potentiate IGF-I activity. Disruption of the signaling pathway by dominant negative mutants of the IGF-I tyrosine kinase receptor or Raf1 have been used in various contexts to evaluate growth factor signaling hierarchy. Dominant negative mutants of SRF and Elk-1, targets for phosphorylation through MAPK, which appear to be required for activation of the SkA promoter, are reputed to be excellent candidates for interrupting final steps in the signaling pathways. This approach would be complemented by over expression of IGF-I, IGFBPs and IGF-I receptor which might act to potentiate the cardiac hypertrophic phenotype. The applicant intends to use the "GeneSwitch" inducible vector system both in the defective adenovirus backbone and transgenic mice to express these important regulatory products in adult cardiac muscle cells as a means to intervene in the signaling process which mediates cardiac hypertrophy.